PROJECT SUMMARY 9 The long-term objective of this R61/R33 is to employ ? -tetrahydrocannibinol (THC) a type 1 cannabinoid receptor (CB1) agonist, as a ?cognitive enhancer? to increase recall of extinction learning in posttraumatic stress disorder (PTSD). First-line psychotherapy for PTSD is Prolonged Exposure (PE), which involves repeated exposure to fear-linked cues to produce ?extinction? of fear. PE is generally effective, but many patients have incomplete extinction or fail to sustain extinction learning-related improvement over time. Recall of extinction learning depends upon limbic-frontal brain networks (hippocampus [HPC], ventromedial prefrontal cortex [vmPFC]) and PTSD patients show decreased activity in these regions and poor extinction recall. Adjunct interventions that address vmPFC-HPC dysfunction and rescue extinction recall deficits could enhance the efficacy of PE for PTSD. Compelling evidence suggests that an acute oral dose of THC, prior to experimental fear extinction procedures in healthy volunteers, facilitates recall of extinction learning via increased activation and functional connectivity of the vmPFC and HPC. As extinction recall deficits and vmPFC-HPC dysfunction have been observed in PTSD, findings indicate the cannabinoid system is a promising target to improve the efficacy and durability of learning during PE in treating PTSD. Accordingly, we will test the hypotheses that THC will significantly enhance the recall of extinction learning in patients with PTSD and reduce symptom severity and that these effects will be mediated via increased activation of the vmPFC and/or HPC. In the R61 phase, PTSD patients will be randomized to one of three conditions (low 5mg THC; high 10mg THC; placebo [PBO]). We will couple a standard Pavlovian fear extinction paradigm with functional MRI (fMRI) and skin conductance recordings (SCR) to compare the effects of THC vs PBO administered prior to extinction learning, testing recall of extinction learning 24 hr and 1 week after extinction learning. If THC (vs. PBO) significantly increases extinction recall and increases vmPFC and/or HPC activation in PTSD, the R33 phase will test the efficacy of THC to reduce PTSD symptom severity, and increase maintenance of treatment following PE. In the R33 phase, PTSD patients will be randomly assigned to a THC (dose identified from R61 phase) or PBO condition. THC or PBO will be administered 2 hr prior to each exposure session in a standard manualized PE treatment protocol. We will assess treatment success (reduced PTSD symptom severity) at each PE visit following THC and again at 3 months after treatment to explore long-term PE effects coupled with THC. Like the R61 phase, we will use a Pavlovian fear extinction paradigm to measure brain activation in fear extinction circuitry during an extinction recall test pre- and post-treatment to determine whether THC increases activation in this circuitry. Together, the R61 and R33 phases will provide the most directly translational and critical test of THC effects in PTSD. Findings from this investigation could stimulate development of novel pharmacological modulators of the cannabinoid system to maximize the efficacy of exposure therapy for PTSD.